Dokument: Charakterisierung der Adhäsion αIIbβ3-transfektierter HEK293-Zellen an immobilisierte Adhäsivproteine (Fibrinogen und Fibronektin)
| Titel: | Charakterisierung der Adhäsion αIIbβ3-transfektierter HEK293-Zellen an immobilisierte Adhäsivproteine (Fibrinogen und Fibronektin) | |||||||
| Weiterer Titel: | Characterization of the adhesion of αIIbβ3-expressing HEK293 cells to immobilized adhesive proteins (fibrinogen and fibronectin) | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=43370 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20170907-111351-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Chahem, Benjamin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. med. Scharf, Rüdiger E. [Betreuer/Doktorvater] Prof. Dr. Gödecke, Axel [Gutachter] Prof. Dr. med. Hohlfeld, Thomas [Gutachter] | |||||||
| Stichwörter: | fibrinogen, fibronectin displacement, shear stress, GpIIbIIIa, HPA-1-polymorphism, flow chamber, integrins, platelets | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Der HPA-1-Polymorphismus des thrombozytären Integrins αIIbβ3 bedingt einen Aminosäurenaustausch von Leucin (Leu33, HPA-1a) zu Prolin (Pro33, HPA-1b) in Position 33 der β-Untereinheit. In vorangegangenen Studien konnte gezeigt werden, dass Patienten mit koronarer Herzkrankheit, die zugleich Träger eines HPA-1b-Allels sind, im Median 5,2 Jahre früher einen Myokardinfarkt erleiden als homozygote HPA-1a-Patienten. Außerdem wiesen αIIbβ3-transfektierte Zellen der HPA-1b-Isoform in Flusskammerversuchen höhere Adhäsionsraten an immobilisiertes Fibrinogen auf.
Ziel dieser Arbeit war, das Adhäsionsverhalten der beiden HPA-1-Varianten gegenüber verschiedenen Liganden in unterschiedlicher Konzentration unter flussdynamischen Bedingungen zu analysieren und zu charakterisieren. Hierzu wurden αIIbβ3-transfektierte HEK293-Zellen und ein Flusskammermodell eingesetzt, das die Applikation variabler Scherraten erlaubt. Die Visualisierung der Zellen erfolgte mit digitalem Imaging. Fluoreszenzmarkierte HEK293-Zellen, die αIIbβ3 entweder in der HPA-1a- oder HPA-1b-Isoform exprimierten, wurden auf mit Fibrinogen oder Fibronektin beschichteten Deckgläsern über eine Minute bei 37 °C und 5 % CO2-Sättigung zur Adhäsion gebracht. Anschließend wurden die Zellen in der Flusskammer schrittweise steigenden Scherraten, die venöse (30 - 500 s-1) und arterielle (1000 - 2000 s-1) Bedingungen simulierten, für je eine Minute exponiert und die Rate noch adhärierter Zellen bestimmt. αIIbβ3 exprimierende Zellen der HPA-1b (Pro33)-Isoform zeigten bei 50 μg/ml Fibrinogen einen signifikant höheren Prozentsatz residueller Zellen unter arteriellen Strömungsbedingungen als die Zellen der HPA-1a (Leu33)-Isoform (p < 0,0001). Dieser Unterschied war mit 100 μg/ml Fibrinogen geringer ausgeprägt, aber immer noch signifikant (p < 0,05). HPA-1b-Isoform exprimierende Zellen wiesen mit 50 μg/ml Fibronektin einen ähnlich hohen Anteil residueller Zellen über alle Scherraten wie bei Verwendung der gleichen Fibrinogenkonzentration auf. Hingegen waren bereits bei venösen Scherraten von 60 s-1 signifikant weniger HPA-1a-Isoform exprimierende Zellen adhärent (p < 0,05). Die gesteigerte Adhäsionsstabilität, die bei Verdopplung der Fibrinogenkonzentration auf 100 μg/ml bei der HPA-1a-Isoform zu verzeichnen war, konnte bei Verwendung von 100 μg/ml Fibronektin nur in einer wesentlich geringeren Ausprägung registriert werden (p < 0,05). Die Versuche zeigen, dass die HPA-1b-Isoform αIIbβ3-transfektierter HEK293-Zellen einen Einfluss auf die Adhäsionsstabilität unter flussdynamischen Bedingungen hat. Die Resistenz gegenüber steigenden Scherraten wird durch den Liganden und seine Konzentration moduliert. Das Adhäsionsverhalten der HPA-1b-Isoform des thrombozytären αIIbβ3-Integrins ist ein Beleg für ihren prothrombotischen Phänotyp.Introduction The HPA-1 polymorphism arises from a leucine-to-proline amino acid substitution at residue 33 of the β3 subunit of αIIbβ3 integrin and results in HPA-1a (Leu33) and HPA-1b (Pro33) isoforms. Studies have shown that compared with HPA-1a homozygotes, carriers of the HPA-1b allele experience coronary artery disease 5.2 years (median) earlier and demonstrate increased adhesion of Pro33-positive cells to fibrinogen under arterial flow conditions. The aim of this study was to compare the adhesion of the 2 HPA-1 isoforms to different ligands in a flow system under increasing shear rates. Material and Methods Fluorescently tagged human embryonic kidney 293 cells (HEK293) stably expressing either the HPA-1a or HPA-1b isoform adhered to fibrinogen- or fibronectin-coated coverslips (50 and 100 µg/ml each) and were subjected to increasing shear rates. Results On 50 µg/ml fibrinogen, Leu33 isoform-expressing cells showed significantly higher displacement at arterial shear rates (1000 and 2000 s-1). The difference in adhesion at high shear rates was smaller but still significant for cells seeded on 100 µg/ml fibrinogen. HPA-1b cells adhered to 50 µg/ml fibronectin with similar kinetics as to fibrinogen, whereas HPA-1a cells revealed significantly increased displacement at shear rates as little as 60 s-1. The positive effect on HPA-1a cell adhesion of doubling the fibronectin concentration was less distinct than for fibrinogen. Conclusion Our data show that the Leu33Pro polymorphism has an important impact on cell adhesion under flow conditions. The adhesion strength and resistance to increasing shear rates is modulated largely by the type and concentration of the ligand. | |||||||
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Online verfügbar unter doi:10.1111/j.1538-7836.2005.01432. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | Beginn der Disseration: 03/2009
Abschluss der Dissertation: 09/2017 | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Hämostaseologie und Transfusionsmedizin | |||||||
| Dokument erstellt am: | 07.09.2017 | |||||||
| Dateien geändert am: | 07.09.2017 | |||||||
| Promotionsantrag am: | 21.10.2014 | |||||||
| Datum der Promotion: | 05.09.2017 |
